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\u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-variant-link\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Ca href=\u0022\/content\/132\/5\/e1327.full-text.pdf\u0022 target=\u0022_blank\u0022 class=\u0022aap-download-pdf link-icon\u0022 title=\u0022Download PDF\u0022\u003E\u003Ci class=\u0022aap-icon-page-pdf\u0022\u003E\u003C\/i\u003E Download PDF\u003C\/a\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003Cdiv class=\u0022panel-separator\u0022\u003E\u003C\/div\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n \n \n \n \u003Cdiv class=\u0022pane-content\u0022\u003E\n \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 data-highwire-cite-ref-tooltip-instance=\u0022highwire_reflinks_tooltip\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003EAbstract\u003C\/h2\u003E\u003Cdiv id=\u0022sec-1\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-1\u0022\u003E\u003Cstrong\u003EOBJECTIVE:\u003C\/strong\u003E To assess off-label use of the topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, in children during periods before and after regulatory action by the US Food and Drug Administration (FDA) in 2005.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-2\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-2\u0022\u003E\u003Cstrong\u003EMETHODS:\u003C\/strong\u003E We identified new pediatric (age \u0026lt;20 years) users of topical tacrolimus or pimecrolimus in US Medicaid from 2001 to 2009, and examined the annual rate of drug use (pre- and postregulatory action) by age. We assessed medical claims for diagnoses consistent with an indication for a TCI, and assessed prescriptions for evidence of first-line atopic dermatitis therapy use before TCI initiation.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-3\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-3\u0022\u003E\u003Cstrong\u003ERESULTS:\u003C\/strong\u003E There were 57\u2009664 eligible pediatric tacrolimus users and 425\u2009242 eligible pediatric pimecrolimus users at baseline. The rate of TCI use decreased substantially after FDA regulatory action. The proportion of new users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001) and pimecrolimus (47.0% to 33.7%, \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001) after regulatory actions. Previous use of topical corticosteroids increased by \u223c7% for both TCIs from the pre- to postregulatory period. However, after regulatory actions, there was only a small increase in the proportion of tacrolimus or pimecrolimus users with an atopic dermatitis or eczema diagnosis before drug initiation, and high strength use of tacrolimus was unchanged.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-4\u0022 class=\u0022subsection\u0022\u003E\u003Cp id=\u0022p-4\u0022\u003E\u003Cstrong\u003ECONCLUSIONS:\u003C\/strong\u003E The rate of TCI use in children younger than 2 years of age fell substantially after FDA regulatory action in 2005. Off-label use of TCI as first-line therapy changed little.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003E\u003Ca href=\u0022\/keyword\/topical-calcineurin-inhibitors\u0022 class=\u0022hw-term hw-article-keyword hw-article-keyword-topical-calcineurin-inhibitors\u0022 rel=\u0022nofollow\u0022\u003Etopical calcineurin inhibitors\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003E\u003Ca href=\u0022\/keyword\/pharmacoepidemiology\u0022 class=\u0022hw-term hw-article-keyword hw-article-keyword-pharmacoepidemiology\u0022 rel=\u0022nofollow\u0022\u003Epharmacoepidemiology\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003E\u003Ca href=\u0022\/keyword\/label-drug-use\u0022 class=\u0022hw-term hw-article-keyword hw-article-keyword-off-label-drug-use\u0022 rel=\u0022nofollow\u0022\u003Eoff-label drug use\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003Cli class=\u0022fn\u0022 id=\u0022glossary-1\u0022\u003EAbbreviations:\u003Cdl id=\u0022def-list-1\u0022\u003E\u003Cdt id=\u0022def-item-1\u0022\u003EAD\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E \u2014 \u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003Eatopic dermatitis\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-2\u0022\u003EFDA\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E \u2014 \u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003EUS Food and Drug Administration\u003Cspan class=\u0022def-item-dd-sep\u0022\u003E\u003C\/span\u003E\u003C\/dd\u003E\u003Cdt id=\u0022def-item-3\u0022\u003ETCI\u003Cspan class=\u0022def-item-dt-sep\u0022\u003E \u2014 \u003C\/span\u003E\u003C\/dt\u003E\u003Cdd\u003Etopical calcineurin inhibitor\u003C\/dd\u003E\u003C\/dl\u003E\u003C\/li\u003E\u003Cdiv class=\u0022boxed-text\u0022 id=\u0022boxed-text-1\u0022\u003E\u003Cdiv id=\u0022sec-5\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EWhat\u2019s Known on This Subject:\u003C\/h4\u003E\u003Cp id=\u0022p-5\u0022\u003EIn January 2006, a public health advisory and boxed warning for long-term safety and the risk of malignancies and a medication guide were issued for topical calcineurin inhibitors, tacrolimus and pimecrolimus.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022boxed-text\u0022 id=\u0022boxed-text-2\u0022\u003E\u003Cdiv id=\u0022sec-6\u0022 class=\u0022subsection\u0022\u003E\u003Ch4\u003EWhat This Study Adds:\u003C\/h4\u003E\u003Cp id=\u0022p-6\u0022\u003EEvaluation of off-label use of topical calcineurin inhibitors in children before and after regulatory action by the Food and Drug Administration is important to understand the impact of regulatory action.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-7\u0022\u003E\u003Cp id=\u0022p-7\u0022\u003EThe topical calcineurin inhibitors (TCIs), tacrolimus (Protopic [Astellas Pharma US, Inc, Northbrook, IL]) and pimecrolimus (Elidel [Meda Pharmaceuticals, Somerset, NJ]), are potent immunosuppressants that act by inhibiting T-lymphocyte activation and the release of proinflammatory cytokines via a calcineurin-mediated pathway.\u003Ca id=\u0022xref-ref-1-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003E\u003Csup\u003E1\u003C\/sup\u003E\u003C\/a\u003E\u003Csup\u003E,\u003C\/sup\u003E\u003Ca id=\u0022xref-ref-2-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003E\u003Csup\u003E2\u003C\/sup\u003E\u003C\/a\u003E Tacrolimus and pimecrolimus were approved by the US Food and Drug Administration (FDA) in December 2000 and 2001, respectively, as second-line therapies for the short and intermittent treatment of mild to moderate atopic dermatitis (AD). Pimecrolimus 1% and tacrolimus 0.03% ointment are indicated for adults and children \u22652 years of age, whereas tacrolimus 0.1% ointment is indicated for adults only.\u003Ca id=\u0022xref-ref-1-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-1\u0022\u003E\u003Csup\u003E1\u003C\/sup\u003E\u003C\/a\u003E\u003Csup\u003E,\u003C\/sup\u003E\u003Ca id=\u0022xref-ref-2-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-2\u0022\u003E\u003Csup\u003E2\u003C\/sup\u003E\u003C\/a\u003E Perhaps not unexpectedly, TCIs have been used off-label in children as first-line treatments for AD, and in children younger than the age of 2.\u003Ca id=\u0022xref-ref-3-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E\u003C\/p\u003E\u003Cp id=\u0022p-8\u0022\u003EOne of the leading safety concerns with TCIs has been whether they might increase the risk of malignancy. During preclinical development, carcinogenicity signals were reported in both mice and monkeys.\u003Ca id=\u0022xref-ref-3-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E Additionally, orally or intravenously administered tacrolimus is associated with an increased risk of lymphoproliferative disorders and skin cancer in transplant recipients.\u003Ca id=\u0022xref-ref-4-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-4\u0022\u003E\u003Csup\u003E4\u003C\/sup\u003E\u003C\/a\u003E Although TCIs are not administered systemically, systemic absorption after topical application has been reported, with increased absorption in AD resulting in greater systemic exposure.\u003Ca id=\u0022xref-ref-3-3\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E\u003Csup\u003E,\u003C\/sup\u003E\u003Ca id=\u0022xref-ref-5-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-5\u0022\u003E\u003Csup\u003E5\u003C\/sup\u003E\u003C\/a\u003E Systemic absorption of TCIs is of particular concern in the pediatric age group, where the ratio of body surface area to weight is greatest. This may explain why detectable blood levels of these drugs are more frequently observed in children than in adults.\u003Ca id=\u0022xref-ref-3-4\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EIn March 2005, the FDA issued a public health advisory warning of a potential malignancy risk with TCIs, and stated that TCIs should be used only as second-line agents, only for short periods of time, and only in children at least 2 years of age.\u003Ca id=\u0022xref-ref-6-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003E\u003Csup\u003E6\u003C\/sup\u003E\u003C\/a\u003E There was a general concern that TCIs were being used increasingly off-label, perhaps due in part to the heavy promotion for use in young children.\u003Ca id=\u0022xref-ref-3-5\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E Supporting data revealed that from June 2003 through May 2004, the number of prescriptions dispensed for topical tacrolimus had increased by 16% and for pimecrolimus by 46%, compared with the previous year. In this same time period, patients aged 1 to 2 years accounted for 8% and 13% of topical tacrolimus and pimecrolimus prescriptions, respectively.\u003Ca id=\u0022xref-ref-3-6\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-3\u0022\u003E\u003Csup\u003E3\u003C\/sup\u003E\u003C\/a\u003E In January 2006, a boxed warning was added to TCI labeling, and a medication guide describing the potential malignancy risk with these products was issued. In March 2006, this warning was sent to prescribing physicians as a \u201cDear Health Care Provider\u201d letter.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003EDespite heightened regulatory activity in 2005\u20132006, the impact of the FDA\u2019s actions on off-label use has not been carefully evaluated in a population-based study. The purpose of this study was to assess off-label use of TCIs in children during periods before and after the FDA\u2019s public health advisory and boxed warning. Specifically, we sought to determine whether off-label use in children \u0026lt;2 years of age and as a first-line therapy decreased after the FDA\u2019s labeling action. The impact of the boxed warning is especially important given that on May 16, 2011, the Pediatric Advisory Committee voted to leave the existing warning given currently available data on malignancy risk.\u003Ca id=\u0022xref-ref-7-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-7\u0022\u003E\u003Csup\u003E7\u003C\/sup\u003E\u003C\/a\u003E\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section methods\u0022 id=\u0022sec-8\u0022\u003E\u003Ch2\u003EMethods\u003C\/h2\u003E\u003Cdiv id=\u0022sec-9\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EStudy Population\u003C\/h3\u003E\u003Cp id=\u0022p-11\u0022\u003EThrough the SafeRx Project, a collaboration between the Centers for Medicare \u0026amp; Medicaid Services and the FDA, a database containing all health care utilization and drug prescription claims for Medicaid recipients from the 50 states and the District of Columbia was created, covering the years 1999 to the present. We identified all pediatric (age \u0026lt;20 years) patients with a prescription for topical tacrolimus or pimecrolimus during the period January 1, 2001, through December 31, 2009. Children age 1 year or older were enrolled in a new-user study cohort if they had at least 183 days of previous continuous Medicaid enrollment and during which they did not have a prescription for a TCI. For children younger than 1 year of age, a minimum of 30 days of previous continuous Medicaid enrollment with no prescription for a TCI was required, thereby also permitting the inclusion of younger children in the study.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EFor each cohort member, demographic and claims data for all inpatient and outpatient medical encounters during the study period were collected, as were prescription data, including the name, strength, and dispensing date for all TCI prescriptions. We excluded children with a previous diagnosis of cancer, HIV\/AIDS, or organ transplantation, or with previous chemotherapy, antiretroviral therapy, or systemic immunosuppressive prescriptions.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv id=\u0022sec-10\u0022 class=\u0022subsection\u0022\u003E\u003Ch3\u003EStatistical Analyses\u003C\/h3\u003E\u003Cp id=\u0022p-13\u0022\u003EWe examined characteristics of tacrolimus and pimecrolimus users, including age and gender. Medical claims within the 183 days before filling of the first TCI prescription (or within 30 days before for children \u0026lt;1 year old) were analyzed for the presence of the AD (\u003Cem\u003EInternational Classification of Diseases, Ninth Revision, Clinical Modification\u003C\/em\u003E code 691), eczema (code 692), other allergic dermatitis (code 693), psoriasis (code 696), allergic conjunctivitis (codes 372.0\u2013372.3), allergic rhinitis (code 477), rash and other nonspecific skin eruptions (code 782.1), impetigo (code 684), and dermatophytosis of the body (code 110.5). We also assessed prescription claims for topical corticosteroid use during the period before TCI use and for use of medications that would not necessarily be expected to precede TCI use including oral corticosteroids, oral antihistamines, asthma inhalers (inhaled \u03b2-agonists), and asthma inhaled corticosteroids. Lastly, we determined the average number of refills per patient within a year, with patients followed until end of continuous fee for service (FFS) Medicaid enrollment, Dec 31, 2009, 1 year after medication initiation, or death.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003EWe estimated the rate of new (incident) tacrolimus and pimecrolimus users per 100\u2009000 children over time according to age category (ie, \u0026lt;1 year, 1 to \u0026lt;2 years, 2\u201319 years), by using Medicaid beneficiaries of the same age meeting the same enrollment requirements as the denominator.\u003C\/p\u003E\u003Cp id=\u0022p-15\u0022\u003EWe also evaluated the proportion of pimecrolimus and tacrolimus users with evidence of off-label use defined by age (\u0026lt;2 years) and initial treatment (no previous treatment with a topical corticosteroid) during the periods before the FDA\u2019s regulatory actions (2001\u20132004) and after (2007\u20132009). The mean number of refills per patient within a year after initiation during these time periods was also examined. The FDA regulatory actions included a public health advisory concerning a potential malignancy risk with TCI exposure issued on March of 2005, a boxed warning and a medication guide describing the potential malignancy risk issued on January of 2006, and a Dear Health Care Provider letter sent to prescribers on March of 2006. \u03c7\u003Csup\u003E2\u003C\/sup\u003E tests were performed to identify statistically significant differences between these time periods.\u003C\/p\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section results\u0022 id=\u0022sec-11\u0022\u003E\u003Ch2\u003EResults\u003C\/h2\u003E\u003Cp id=\u0022p-16\u0022\u003EFrom 2001 to 2009, we identified 58\u2009648 and 429\u2009495 children who initiated treatment with topical tacrolimus or pimecrolimus, respectively. Of these, 984 and 4253 were excluded due to other diagnoses (\u003Cem\u003En\u003C\/em\u003E = 772 and 3225) or being in pediatric nursing facilities (\u003Cem\u003En\u003C\/em\u003E = 212 and 1028). Thus we identified 57\u2009664 eligible children who initiated treatment with topical tacrolimus and 425\u2009242 with topical pimecrolimus. TCI use did not differ by gender, and the mean age of pediatric users was similar for both drugs (\u003Ca id=\u0022xref-table-wrap-1-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T1\u0022\u003ETable 1\u003C\/a\u003E). The majority of users (64.3% of tacrolimus; 76.4% of pimecrolimus) did not have a diagnosis of AD or eczema during the preinitiation period. The presence of a diagnosis of psoriasis, allergic conjunctivitis, allergic rhinitis, and rash and other nonspecific skin eruptions was relatively infrequent across both cohorts. Use of topical corticosteroids before TCI initiation was low for both products (39.5% for tacrolimus; 21.2% for pimecrolimus). Mean tacrolimus refills within a year after initiation were slightly higher than mean pimecrolimus refills after initiation (tacrolimus: \u0026lt;2 years, 1.75 refills; \u22652 years, 1.87 refills; pimecrolimus: \u0026lt;2 years, 1.63 refills; \u22652 years, 1.62 refills). Average follow-up time ranged from 250.8 days to 296.7 days.\u003C\/p\u003E\u003Cdiv class=\u0022table pos-float\u0022 id=\u0022T1\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/7718\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/7718\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\n\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETABLE 1\u003C\/span\u003E \u003Cp id=\u0022p-31\u0022 class=\u0022first-child\u0022\u003ECharacteristics of Pediatric Study Cohort, 2001\u20132009\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-17\u0022\u003EThe rate of initiation of tacrolimus and pimecrolimus rapidly increased in children \u0026lt;2 years of age within a short time after drug approval (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigs 1\u003C\/a\u003E and \u003Ca id=\u0022xref-fig-2-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F2\u0022\u003E2\u003C\/a\u003E). The rate of initiation of both products was higher among children \u0026lt;1 year and 1 to \u0026lt;2 years than among those age 2 to 19 years across the entire study period, with the exception of pimecrolimus use in children \u0026lt;1 year in 2009. For both tacrolimus and pimecrolimus, rates of initiation among \u0026lt;1 year and 1 to \u0026lt;2 year olds followed similar patterns over time. For both age groups, the rate of tacrolimus initiation peaked in 2003\/2004 (\u0026lt;1 year: 368.9 per 100\u2009000; 1 to \u0026lt;2 years: 383.5 per 100\u2009000), and the rate of pimecrolimus initiation peaked in 2004 (\u0026lt;1 year: 5449.3 per 100\u2009000; 1 to \u0026lt;2 years: 4601.8 per 100\u2009000). The rates of initiation of both products in children age \u0026lt;1 year and age 1 to \u0026lt;2 years dropped markedly in 2005, the year of the public health advisory, and dropped again in 2006, the year the boxed warning was issued. Rates of tacrolimus and pimecrolimus initiation among children age 2 to 19 years also decreased post regulatory actions. Although the rate of initiation of both medications decreased post regulatory action, the mean number of prescriptions within a year after initiation appeared relatively stable for the pre- and postregulatory periods for both age groups (tacrolimus users: \u0026lt;2 years, 2.6 vs 2.3; 2+ years, 2.4 vs 2.2; pimecrolimus users: \u0026lt;2 years, 2.5 vs 2.1; 2+ years: 2.0 vs 1.9).\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Rate of initiation of tacrolimus among beneficiaries \u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1790623223\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Rate of initiation of tacrolimus among beneficiaries \u0026lt;20 years by age and calendar year, Medicaid 2001\u0026#x2013;2009.\u0026lt;\/div\u0026gt;\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIGURE 1\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F1.medium.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIGURE 1\u0022 src=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F1.medium.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download FIGURE 1\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022new-tab\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/7689\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\n\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIGURE 1\u003C\/span\u003E \u003Cp id=\u0022p-33\u0022 class=\u0022first-child\u0022\u003ERate of initiation of tacrolimus among beneficiaries \u0026lt;20 years by age and calendar year, Medicaid 2001\u20132009.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv id=\u0022F2\u0022 class=\u0022fig pos-float type-figure odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F2.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Rate of initiation of pimecrolimus among beneficiaries \u0022 class=\u0022highwire-fragment fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1790623223\u0022 data-figure-caption=\u0022\u0026lt;div class=\u0026quot;highwire-markup\u0026quot;\u0026gt;Rate of initiation of pimecrolimus among beneficiaries \u0026lt;20 years by age and calendar year, Medicaid 2001\u0026#x2013;2009.\u0026lt;\/div\u0026gt;\u0022\u003E\u003Cspan class=\u0022hw-responsive-img\u0022\u003E\u003Cimg class=\u0022highwire-fragment fragment-image lazyload\u0022 alt=\u0022FIGURE 2\u0022 src=\u0022data:image\/gif;base64,R0lGODlhAQABAIAAAAAAAP\/\/\/yH5BAEAAAAALAAAAAABAAEAAAIBRAA7\u0022 data-src=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F2.medium.gif\u0022\/\u003E\u003Cnoscript\u003E\u003Cimg class=\u0022highwire-fragment fragment-image\u0022 alt=\u0022FIGURE 2\u0022 src=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F2.medium.gif\u0022\/\u003E\u003C\/noscript\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u0022download-fig first\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F2.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download FIGURE 2\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022new-tab\u0022\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/pediatrics\/132\/5\/e1327\/F2.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022download-ppt last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/7646\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\n\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFIGURE 2\u003C\/span\u003E \u003Cp id=\u0022p-34\u0022 class=\u0022first-child\u0022\u003ERate of initiation of pimecrolimus among beneficiaries \u0026lt;20 years by age and calendar year, Medicaid 2001\u20132009.\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-18\u0022\u003E\u003Ca id=\u0022xref-table-wrap-2-1\u0022 class=\u0022xref-table\u0022 href=\u0022#T2\u0022\u003ETable 2\u003C\/a\u003E reveals the characteristics of tacrolimus and pimecrolimus use before and after regulatory action. The proportion of tacrolimus users with a previous AD or eczema diagnosis increased little after regulatory action (33.2% to 34.5%), whereas for pimecrolimus there was a slightly larger increase (20.7% to 25.8%). A sensitivity analysis using a 365-day window revealed only a small increase in the percentage of AD or eczema diagnoses (data not shown). Previous use of a topical corticosteroid increased by \u223c7% for both tacrolimus and pimecrolimus from the pre- to postregulatory period. Nonetheless, during the period after regulatory actions, most children still did not receive topical corticosteroids before initiating a TCI. The proportion of users younger than 2 years of age significantly decreased for both tacrolimus (36.7% to 22.5%, \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001) and pimecrolimus (47.0% to 33.7%, \u003Cem\u003EP\u003C\/em\u003E \u0026lt; .001) after the regulatory actions. Of note, the contraindicated use of the higher strength tacrolimus ointment (0.03%) among children younger than age 2 years remained essentially unchanged.\u003C\/p\u003E\u003Cdiv class=\u0022table pos-float\u0022 id=\u0022T2\u0022\u003E\u003Cdiv class=\u0022table-inline table-callout-links\u0022\u003E\u003Cdiv class=\u0022callout\u0022\u003E\u003Cspan\u003EView this table:\u003C\/span\u003E\u003Cul class=\u0022callout-links\u0022\u003E\u003Cli class=\u0022view-inline first\u0022\u003E\u003Ca href=\u0022##\u0022 class=\u0022table-expand-inline\u0022 data-table-url=\u0022\/highwire\/markup\/7693\/expansion?postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0026amp;table-expand-inline=1\u0022\u003EView inline\u003C\/a\u003E\u003C\/li\u003E\n\u003Cli class=\u0022view-popup last\u0022\u003E\u003Ca href=\u0022\/highwire\/markup\/7693\/expansion?width=1000\u0026amp;height=500\u0026amp;iframe=true\u0026amp;postprocessors=highwire_tables%2Chighwire_reclass%2Chighwire_figures%2Chighwire_math%2Chighwire_inline_linked_media%2Chighwire_embed\u0022 class=\u0022colorbox colorbox-load table-expand-popup\u0022 rel=\u0022gallery-fragment-tables\u0022\u003EView popup\u003C\/a\u003E\u003C\/li\u003E\n\u003C\/ul\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022table-caption\u0022\u003E\u003Cspan class=\u0022table-label\u0022\u003ETABLE 2\u003C\/span\u003E \u003Cp id=\u0022p-35\u0022 class=\u0022first-child\u0022\u003ECharacteristics of Tacrolimus and Pimecrolimus Use, Pre- (2001\u20132004) and Postregulatory (2007\u20132009) Action\u003C\/p\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section discussion\u0022 id=\u0022sec-12\u0022\u003E\u003Ch2\u003EDiscussion\u003C\/h2\u003E\u003Cp id=\u0022p-19\u0022\u003EWe observed large decreases in the rate of new use of tacrolimus and pimecrolimus in the Medicaid pediatric population coincident with FDA regulatory actions in 2005 and 2006. In particular, there was an abrupt decrease in off-label use by children younger than 2 years of age. Although we cannot definitively attribute these decreases to specific FDA actions or publicity surrounding these actions, the decreases appear to coincide with the FDA\u2019s public health advisory and boxed warning, which emphasized the potential risk of malignancy and that use among children younger than 2 years of age was not an approved use.\u003Ca id=\u0022xref-ref-6-2\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-6\u0022\u003E\u003Csup\u003E6\u003C\/sup\u003E\u003C\/a\u003E Although off-label TCI use in children younger than 2 years of age decreased after FDA regulatory action, the rate of use remained slightly higher than or similar to the rate observed in children \u0026gt;2 years. Additionally, use of the higher strength tacrolimus (0.1%) ointment among children \u0026lt;2 years, which is indicated for patients \u0026gt;15 years only, did not change. The FDA\u2019s regulatory actions also did not lead to a marked reduction in off-label use of these products as first-line therapies. This is particularly concerning given that this type of off-label use could result in children not receiving the most effective and safest drug in an appropriate manner.\u003Ca id=\u0022xref-ref-8-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-8\u0022\u003E\u003Csup\u003E8\u003C\/sup\u003E\u003C\/a\u003E Although the increase in use of topical corticosteroids before TCI initiation in the period after FDA regulatory action was statistically significant, it is likely to have negligible public health impact, with most children not being treated with them before TCI therapy initiation. The magnitude of this off-label use was greater for pimecrolimus than tacrolimus. This could be explained by varying indications for the 2 drugs with pimecrolimus indicated for mild to moderate AD and tacrolimus indicated for moderate to severe AD. There was little or no increase in the proportion of children having a diagnosis of AD or eczema before starting tacrolimus or pimecrolimus after the FDA\u2019s regulatory action, and even then, most children did not have 1 of these diagnoses during the baseline period. Given the relatively short prior-use window of 183 days used in primary analyses, we may not have captured all diagnoses; a sensitivity analysis using a 365-day window only revealed a small increase in the percentage of AD or eczema diagnoses. Additionally, the sensitivity and the specificity of the \u003Cem\u003EInternational Classification of Diseases, Ninth Revision, Clinical Modification\u003C\/em\u003E codes used to capture AD or eczema has not been established.\u003C\/p\u003E\u003Cp id=\u0022p-20\u0022\u003ETwo previous studies examined the use of TCIs in children. One study, published in abstract form only, revealed substantial declines in TCI use by children younger than the age of 2 in 2005 and again in 2007, using a pharmacy claims database.\u003Ca id=\u0022xref-ref-9-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-9\u0022\u003E\u003Csup\u003E9\u003C\/sup\u003E\u003C\/a\u003E The other was a cross-sectional study that examined the prescription of TCIs in visits for AD by children (0\u201318 years) by using the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Care Survey databases.\u003Ca id=\u0022xref-ref-10-1\u0022 class=\u0022xref-bibr\u0022 href=\u0022#ref-10\u0022\u003E\u003Csup\u003E10\u003C\/sup\u003E\u003C\/a\u003E The study revealed that topical tacrolimus was prescribed in 0.5 million (10%) and topical pimecrolimus was prescribed in 0.6 million (13%) of the 4.6 million AD visits in 2001 to 2004. The study also noted off-label use in children younger than 2 years, with TCIs prescribed in 22% of visits to office-based physicians or hospital outpatient departments in children younger than 2 years.\u003C\/p\u003E\u003Cp id=\u0022p-21\u0022\u003EThere were several important limitations to our study. Although we used a nation-wide cohort of pediatric patients from Medicaid, these differ from the general (non-Medicaid) population in terms of socioeconomic status and may carry a higher burden of medical comorbidities. Given the current AD treatment options, however, we do not expect that these differences would affect the TCI usage patterns we observed. There is also concern that the quality of medical care provided through Medicaid might be different than that available through the private sector, and that physicians who treat large numbers of Medicaid patients may differ in background and training from physicians treating privately insured patients. The potential impact of this concern on the generalizability of our results could be addressed by repeating this analysis in a privately insured population.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section conclusions\u0022 id=\u0022sec-13\u0022\u003E\u003Ch2\u003EConclusions\u003C\/h2\u003E\u003Cp id=\u0022p-22\u0022\u003EOff-label use of TCIs in children younger than 2 years of age decreased substantially in association with FDA regulatory actions, with the exception of the higher strength tacrolimus ointment. However, off-label use of TCIs as a first-line therapy in pediatric patients did not decrease and continues to remain a concern.\u003C\/p\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section fn-group\u0022 id=\u0022fn-group-1\u0022\u003E\u003Ch2\u003EFootnotes\u003C\/h2\u003E\u003Cul\u003E\u003Cul class=\u0022history-list\u0022\u003E\u003Cli xmlns:hwp=\u0022http:\/\/schema.highwire.org\/Journal\u0022 class=\u0022accepted\u0022 hwp:start=\u00222013-08-16\u0022\u003E\u003Cspan class=\u0022accepted-label\u0022\u003EAccepted \u003C\/span\u003EAugust 16, 2013.\u003C\/li\u003E\u003C\/ul\u003E\u003Cli class=\u0022corresp\u0022 id=\u0022corresp-1\u0022\u003EAddress correspondence to Angelika D. Manthripragada, PhD, Center for Observational Research, Amgen Inc, One Amgen Dr, Thousand Oaks, CA 91320. E-mail: \u003Cspan class=\u0022em-link\u0022\u003E\u003Cspan class=\u0022em-addr\u0022\u003Eawahnerm{at}amgen.com\u003C\/span\u003E\u003C\/span\u003E\u003C\/li\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-1\u0022\u003E\u003Cp id=\u0022p-26\u0022\u003EDr Manthripragada conceptualized and designed the study and drafted the initial manuscript; Dr Pinheiro conceptualized and designed the study and reviewed and revised the manuscript; Dr MaCurdy oversaw the analysis and critically reviewed the manuscript; Mr Saneinejad and Mr Worrall carried out the analysis and critically reviewed the manuscript; Dr Kelman oversaw the analysis and critically reviewed the manuscript; Dr Graham conceptualized and designed the study and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn-other\u0022 id=\u0022fn-2\u0022\u003E\u003Cp id=\u0022p-27\u0022\u003EThe views expressed in this manuscript do not necessarily represent those of the US Food and Drug Administration.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn-financial-disclosure\u0022 id=\u0022fn-3\u0022\u003E\u003Cp id=\u0022p-28\u0022\u003E\u003Cstrong\u003EFINANCIAL DISCLOSURE:\u003C\/strong\u003E Dr Manthripragada has stock ownership in Amgen, Inc; the other authors have indicated they have no financial relationships relevant to this article to disclose.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn-supported-by\u0022 id=\u0022fn-4\u0022\u003E\u003Cp id=\u0022p-29\u0022\u003E\u003Cstrong\u003EFUNDING:\u003C\/strong\u003E No external funding.\u003C\/p\u003E\u003C\/li\u003E\u003Cli class=\u0022fn\u0022 id=\u0022fn-5\u0022\u003E\u003Cp id=\u0022p-30\u0022\u003E\u003Cstrong\u003EPOTENTIAL CONFLICT OF INTEREST:\u003C\/strong\u003E Dr Manthripragada is now an employee of Amgen, Inc. Dr Manthripragada was an employee of the US Food and Drug Administration when the analyses for and draft of this manuscript were completed; the other authors have indicated they have no potential conflicts of interest to disclose.\u003C\/p\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022section ref-list\u0022 id=\u0022ref-list-1\u0022\u003E\u003Ch2\u003EReferences\u003C\/h2\u003E\u003Col class=\u0022cit-list\u0022\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-1-1\u0022 title=\u0022View reference 1 in text\u0022 id=\u0022ref-1\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-132.5.e1327.1\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EElidel (pimecrolimus) Cream 1% [package insert]. Quebec, Canada: Valeant Pharmaceuticals International, Inc; 2010. Available at: \u003Ca href=\u0022http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/021302s014lbl.pdf\u0022\u003Ewww.accessdata.fda.gov\/drugsatfda_docs\/label\/2010\/021302s014lbl.pdf\u003C\/a\u003E. Accessed November 22, 2011\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-2-1\u0022 title=\u0022View reference 2 in text\u0022 id=\u0022ref-2\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-132.5.e1327.2\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EProtopic (tacrolimus) Ointment [package insert]. Northbrook, IL: Astellas Pharmaceuticals US, Inc; 2011. Available at: \u003Ca href=\u0022http:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/050777s018lbl.pdf\u0022\u003Ewww.accessdata.fda.gov\/drugsatfda_docs\/label\/2011\/050777s018lbl.pdf\u003C\/a\u003E. Accessed November 22, 2011\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-3-1\u0022 title=\u0022View reference 3 in text\u0022 id=\u0022ref-3\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-132.5.e1327.3\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EDivision of Pediatric Drug Development. Protopic and Elidel presentation for regulatory briefing on January 14, 2005. Available at: \u003Ca href=\u0022http:\/\/www.fda.gov\/ohrms\/dockets\/ac\/05\/briefing\/2005-4089b2_01_02_DPDD%20Consult.pdf\u0022\u003Ewww.fda.gov\/ohrms\/dockets\/ac\/05\/briefing\/2005-4089b2_01_02_DPDD%20Consult.pdf\u003C\/a\u003E. 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March 22, 2010. Available at: \u003Ca href=\u0022http:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/PediatricAdvisoryCommittee\/UCM208036.pdf\u0022\u003Ewww.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/PediatricAdvisoryCommittee\/UCM208036.pdf\u003C\/a\u003E. Accessed May 31, 2011\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-6-1\u0022 title=\u0022View reference 6 in text\u0022 id=\u0022ref-6\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-other\u0022 id=\u0022cit-132.5.e1327.6\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EFDA Public Health Advisory. Elidel (pimecrolimus) cream and Protopic (tacrolimus) ointment. Press release (March 10, 2005). Washington, DC: US Food and Drug Administration\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-7-1\u0022 title=\u0022View reference 7 in text\u0022 id=\u0022ref-7\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-web\u0022 id=\u0022cit-132.5.e1327.7\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EMinutes of the Pediatric Advisory Committee. May 16, 2011. Available at: \u003Ca href=\u0022http:\/\/www.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/PediatricAdvisoryCommittee\/UCM261384.pdf\u0022\u003Ewww.fda.gov\/downloads\/AdvisoryCommittees\/CommitteesMeetingMaterials\/PediatricAdvisoryCommittee\/UCM261384.pdf\u003C\/a\u003E. Accessed November 22, 2011\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-8-1\u0022 title=\u0022View reference 8 in text\u0022 id=\u0022ref-8\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-132.5.e1327.8\u0022 data-doi=\u002210.1136\/archdischild-2011-300293\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Col class=\u0022cit-auth-list\u0022\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EBonati\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EM\u003C\/span\u003E\u003C\/span\u003E, \u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EPandolfini\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EC\u003C\/span\u003E\u003C\/span\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003Ccite\u003E. \u003Cspan class=\u0022cit-article-title\u0022\u003EOff-label drug use in children should be rational.\u003C\/span\u003E \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EArch Dis Child\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-pub-date\u0022\u003E2011\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E96\u003C\/span\u003E(\u003Cspan class=\u0022cit-issue\u0022\u003E9\u003C\/span\u003E):\u003Cspan class=\u0022cit-fpage\u0022\u003E870\u003C\/span\u003E\u2013\u003Cspan class=\u0022cit-lpage\u0022\u003E871\u003C\/span\u003E\u003Cspan class=\u0022cit-pub-id cit-pub-id-pmid\u0022\u003E\u003Cspan class=\u0022cit-pub-id-scheme-pmid\u0022\u003Epmid:\u003C\/span\u003E21715392\u003C\/span\u003E\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DArch%2BDis%2BChild%26rft_id%253Dinfo%253Adoi%252F10.1136%252Farchdischild-2011-300293%26rft_id%253Dinfo%253Apmid%252F21715392%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6MTI6ImFyY2hkaXNjaGlsZCI7czo1OiJyZXNpZCI7czo4OiI5Ni85Lzg3MCI7czo0OiJhdG9tIjtzOjI4OiIvcGVkaWF0cmljcy8xMzIvNS9lMTMyNy5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-9-1\u0022 title=\u0022View reference 9 in text\u0022 id=\u0022ref-9\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-confproc\u0022 id=\u0022cit-132.5.e1327.9\u0022\u003E\u003Cdiv class=\u0022cit-metadata unstructured\u0022\u003EMoeny D, La Grenade L, Brinker A. Changes in topical calcineurin use following regulatory action in the US. In: 25th International Conference for Pharmacoepidemiology; August 16\u201319, 2009; RI\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003Cli\u003E\u003Ca class=\u0022rev-xref-ref\u0022 href=\u0022#xref-ref-10-1\u0022 title=\u0022View reference 10 in text\u0022 id=\u0022ref-10\u0022\u003E\u21b5\u003C\/a\u003E\u003Cdiv class=\u0022cit ref-cit ref-journal\u0022 id=\u0022cit-132.5.e1327.10\u0022 data-doi=\u002210.1542\/peds.2007-0289\u0022\u003E\u003Cdiv class=\u0022cit-metadata\u0022\u003E\u003Col class=\u0022cit-auth-list\u0022\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003EHorii\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EKA\u003C\/span\u003E\u003C\/span\u003E, \u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESimon\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003ESD\u003C\/span\u003E\u003C\/span\u003E, \u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ELiu\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EDY\u003C\/span\u003E\u003C\/span\u003E, \u003C\/li\u003E\u003Cli\u003E\u003Cspan class=\u0022cit-auth\u0022\u003E\u003Cspan class=\u0022cit-name-surname\u0022\u003ESharma\u003C\/span\u003E \u003Cspan class=\u0022cit-name-given-names\u0022\u003EV\u003C\/span\u003E\u003C\/span\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003Ccite\u003E. \u003Cspan class=\u0022cit-article-title\u0022\u003EAtopic dermatitis in children in the United States, 1997-2004: visit trends, patient and provider characteristics, and prescribing patterns.\u003C\/span\u003E \u003Cabbr class=\u0022cit-jnl-abbrev\u0022\u003EPediatrics\u003C\/abbr\u003E. \u003Cspan class=\u0022cit-pub-date\u0022\u003E2007\u003C\/span\u003E;\u003Cspan class=\u0022cit-vol\u0022\u003E120\u003C\/span\u003E(\u003Cspan class=\u0022cit-issue\u0022\u003E3\u003C\/span\u003E). Available at: \u003Ca href=\u0022http:\/\/www.pediatrics.org\/cgi\/content\/full\/120\/3\/e527\u0022\u003Ewww.pediatrics.org\/cgi\/content\/full\/120\/3\/e527\u003C\/a\u003E\u003Cspan class=\u0022cit-pub-id cit-pub-id-pmid\u0022\u003E\u003Cspan class=\u0022cit-pub-id-scheme-pmid\u0022\u003Epmid:\u003C\/span\u003E17766497\u003C\/span\u003E\u003C\/cite\u003E\u003C\/div\u003E\u003Cdiv class=\u0022cit-extra\u0022\u003E\u003Ca href=\u0022{openurl}?query=rft.jtitle%253DPediatrics%26rft.stitle%253DPediatrics%26rft.issn%253D0031-4005%26rft.aulast%253DHorii%26rft.auinit1%253DK.%2BA.%26rft.volume%253D120%26rft.issue%253D3%26rft.spage%253De527%26rft.epage%253De534%26rft.atitle%253DAtopic%2BDermatitis%2Bin%2BChildren%2Bin%2Bthe%2BUnited%2BStates%252C%2B1997%2B2004%253A%2BVisit%2BTrends%252C%2BPatient%2Band%2BProvider%2BCharacteristics%252C%2Band%2BPrescribing%2BPatterns%26rft_id%253Dinfo%253Adoi%252F10.1542%252Fpeds.2007-0289%26rft_id%253Dinfo%253Apmid%252F17766497%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url\u0022\u003E\u003Cspan\u003EOpenUrl\u003C\/span\u003E\u003C\/a\u003E\u003Ca href=\u0022\/lookup\/ijlink\/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6InBlZGlhdHJpY3MiO3M6NToicmVzaWQiO3M6MTA6IjEyMC8zL2U1MjciO3M6NDoiYXRvbSI7czoyODoiL3BlZGlhdHJpY3MvMTMyLzUvZTEzMjcuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9\u0022 class=\u0022cit-ref-sprinkles cit-ref-sprinkles-ijlink\u0022\u003E\u003Cspan\u003E\u003Cspan class=\u0022cit-reflinks-abstract\u0022\u003EAbstract\u003C\/span\u003E\u003Cspan class=\u0022cit-sep cit-reflinks-variant-name-sep\u0022\u003E\/\u003C\/span\u003E\u003Cspan class=\u0022cit-reflinks-full-text\u0022\u003E\u003Cspan class=\u0022free-full-text\u0022\u003EFREE \u003C\/span\u003EFull Text\u003C\/span\u003E\u003C\/span\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/li\u003E\u003C\/ol\u003E\u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003ECopyright \u00a9 2013 by the American Academy of Pediatrics\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/pediatrics.aappublications.org\/content\/132\/5\/e1327.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022\u003EView Abstract\u003C\/a\u003E\u003C\/div\u003E \u003C\/div\u003E\n\n \n \u003C\/div\u003E\n\u003C\/div\u003E\n \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 defer=\u0022defer\u0022 src=\u0022http:\/\/pediatrics.aappublications.org\/sites\/all\/libraries\/lazysizes\/lazysizes.min.js?pd78in\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/pediatrics.aappublications.org\/sites\/default\/files\/js\/js_m8rp0bqt1QmsUsFd7IDvfeYd70dlseIGPGJME-vI8kU.js\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}